The interplay between mitochondria-endoplasmic reticulum contacts and Alzheimer’s disease
Author: Santos Leal, Nuno João
Date: 2019-04-26
Location: Biomedicum 1, Floor 3, Solnavägen 9, Karolinska institutet, Solna
Time: 09.30
Department: Inst för neurobiologi, vårdvetenskap och samhälle / Dept of Neurobiology, Care Sciences and Society
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Thesis (8.284Mb)
Abstract
Even though Alzheimer’s disease (AD) was first described more than 100 years ago, we still have no treatment preventing the ongoing neurodegenerative process. Two major pathological hallmarks have been connected to AD: extracellular amyloid plaques (constituted by amyloid β-peptide – Aβ) and neurofibrillary tangles. Several biological processes have been shown to be altered in AD including mitochondrial functions, autophagosome formation and calcium (Ca2+) homeostasis. Interestingly, all these processes have been shown to be regulated in mitochondria-endoplasmic reticulum contact sites (MERCS). Moreover, both the activity and the number of these contacts are affected in AD, which could explain the alterations of the biological processes mentioned above. However, it is still unknown if the alteration in MERCS causes the pathology or vice-versa. In this thesis, I have contributed to uncovering some of the mechanisms behind the interplay between MERCS and AD.
• In Study I we show that the number of MERCS is increased in brain biopsies of demented patients and that there is a reversed correlation between MERCS and Mini Mental State Examination (MMSE) scores. In the same study, we show that the number of MERCS positively correlate with aging and ventricular Aβ42 levels; • In Study II we show that Aβ increases the number of MERCS in different models, leading to alteration in autophagosome formation and mitochondrial function; • In Study III we show that the increase of MERCS, through acute knock-down of Mitofusin 2, leads to decreased levels of both Aβ40 and Aβ42 due to impaired g-secretase assembly and activity; • In Study IV we show that the translocase of the outer mitochondrial membrane (TOM) receptor protein TOM70 modulates Ca2+ shuttling from ER to mitochondria via IP3R3 at MERCS.
Altogether, these studies contributed to unravel the role of MERCS in AD. We show that MERCS dynamics changes throughout ageing and is accentuated in AD pathology, affecting several biological processes vital for overall cellular function. We believe this increase of MERCS could either trigger the neurodegenerative processes underlying AD or being an attempt to rescue neuronal dysfunctions. Moreover, MERCS modulation affects Aβ levels, which makes us believe that MERCS and Aβ regulate each other in a reciprocal manner.
• In Study I we show that the number of MERCS is increased in brain biopsies of demented patients and that there is a reversed correlation between MERCS and Mini Mental State Examination (MMSE) scores. In the same study, we show that the number of MERCS positively correlate with aging and ventricular Aβ42 levels; • In Study II we show that Aβ increases the number of MERCS in different models, leading to alteration in autophagosome formation and mitochondrial function; • In Study III we show that the increase of MERCS, through acute knock-down of Mitofusin 2, leads to decreased levels of both Aβ40 and Aβ42 due to impaired g-secretase assembly and activity; • In Study IV we show that the translocase of the outer mitochondrial membrane (TOM) receptor protein TOM70 modulates Ca2+ shuttling from ER to mitochondria via IP3R3 at MERCS.
Altogether, these studies contributed to unravel the role of MERCS in AD. We show that MERCS dynamics changes throughout ageing and is accentuated in AD pathology, affecting several biological processes vital for overall cellular function. We believe this increase of MERCS could either trigger the neurodegenerative processes underlying AD or being an attempt to rescue neuronal dysfunctions. Moreover, MERCS modulation affects Aβ levels, which makes us believe that MERCS and Aβ regulate each other in a reciprocal manner.
List of papers:
I. Nuno Santos Leal, Giacomo Dentoni, Bernadette Schreiner, Olli-Pekka Kämäräinen, Nelli Partanen, Sanna-Kaisa Herukka, Anne M Koivisto, Mikko Hiltunen, Tuomas Rauramaa, Ville Leinonen and Maria Ankarcrona. Alterations in mitochondria-endoplasmic reticulum connectivity in human brain biopsies from idiopathic normal pressure hydrocephalus patients. Acta Neuropathol Commun. 2018 Oct 1;6(1):102.
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II. Nuno Santos Leal, Giacomo Dentoni, Bernadette Schreiner, Giovanni Meli, Gabriele Turacchio, Antonio Piras, Caroline Graff, Tamotsu Yoshimori, Maho Hamasaki, Per Nilsson and Maria Ankarcrona. Amyloid β-peptide increases mitochondria-ER contacts and affects mitochondria function and autophagosome formation. [Manuscript]
III. Nuno Santos Leal, Bernadette Schreiner, Catarina Moreira Pinho, Riccardo Filadi, Birgitta Wiehager, Helena Karlström, Paola Pizzo and Maria Ankarcrona. Mitofusin-2 Knockdown Increases ER-Mitochondria Contact and Decreases Amyloid β-Peptide Production. J Cell Mol Med. 2016 Sep;20(9):1686-95.
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IV. Riccardo Filadi, Nuno Santos Leal, Bernadette Schreiner, Alice Rossi, Giacomo Dentoni, Catarina Moreira Pinho, Birgitta Wiehager, Domenico Cieri, Tito Calì, Paola Pizzo and Maria Ankarcrona. TOM70 Sustains Cell Bioenergetics by Promoting IP3R3-Mediated ER to Mitochondria Ca2+Transfer. Curr Biol. 2018 Feb 5;28(3):369-382.e6.
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I. Nuno Santos Leal, Giacomo Dentoni, Bernadette Schreiner, Olli-Pekka Kämäräinen, Nelli Partanen, Sanna-Kaisa Herukka, Anne M Koivisto, Mikko Hiltunen, Tuomas Rauramaa, Ville Leinonen and Maria Ankarcrona. Alterations in mitochondria-endoplasmic reticulum connectivity in human brain biopsies from idiopathic normal pressure hydrocephalus patients. Acta Neuropathol Commun. 2018 Oct 1;6(1):102.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Nuno Santos Leal, Giacomo Dentoni, Bernadette Schreiner, Giovanni Meli, Gabriele Turacchio, Antonio Piras, Caroline Graff, Tamotsu Yoshimori, Maho Hamasaki, Per Nilsson and Maria Ankarcrona. Amyloid β-peptide increases mitochondria-ER contacts and affects mitochondria function and autophagosome formation. [Manuscript]
III. Nuno Santos Leal, Bernadette Schreiner, Catarina Moreira Pinho, Riccardo Filadi, Birgitta Wiehager, Helena Karlström, Paola Pizzo and Maria Ankarcrona. Mitofusin-2 Knockdown Increases ER-Mitochondria Contact and Decreases Amyloid β-Peptide Production. J Cell Mol Med. 2016 Sep;20(9):1686-95.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Riccardo Filadi, Nuno Santos Leal, Bernadette Schreiner, Alice Rossi, Giacomo Dentoni, Catarina Moreira Pinho, Birgitta Wiehager, Domenico Cieri, Tito Calì, Paola Pizzo and Maria Ankarcrona. TOM70 Sustains Cell Bioenergetics by Promoting IP3R3-Mediated ER to Mitochondria Ca2+Transfer. Curr Biol. 2018 Feb 5;28(3):369-382.e6.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Ankarcrona, Maria
Co-supervisor: Karlström, Helena; Winblad, Bengt; Nilsson, Per
Issue date: 2019-03-22
Rights:
Publication year: 2019
ISBN: 978-91-7831-389-1
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